One therapeutic goal in cystic fibrosis and other pulmonary diseases in which the water content of lung mucus is altered is to hydrate the lung mucus secretions, so that the secretions may thereafter be more easily removed from the lungs by mucociliary action or simple coughing. For example, the use of aerosolized amiloride to hydrate mucus secretions is described in U.S. Pat. No. 4,501,729 to Boucher et al. Amiloride appears to block Na.sup.+ reabsorption by airway epithelial cells, and therefore inhibits water absorption from the mucus. While an important breakthrough in providing treatments for cystic fibrosis, a potential problem with amiloride as a therapeutic is its relatively short duration of action.
In certain lung diseases (e.g., cystic fibrosis), several functions of airway epithelia are abnormal, and deficiencies in both Cl.sup.- transport and Na.sup.+ absorption are well documented. See, e.g. Knowles et al., Science 221, 1067 (1983); Knowles et al., J. Clin. Invest. 71, 1410 (1983). Regulation of ion transport is thus thought to have potential therapeutic benefit in lung diseases characterized by abnormalities in epithelial ion transport. Confirmation of the presence of P2Y.sub.2 (P.sub.2U -purinergic) receptors on the apical surface of human airway epithelial cells raised the possibility that aerosolized nucleotides might be used therapeutically to induce Cl.sup.- secretion in individuals with cystic fibrosis or other airway diseases. Accordingly, a different therapeutic approach for hydrating lung mucus secretions is exemplified by techniques that involve the administration of ATP or UTP, which appear to stimulate chloride secretion from respiratory epithelial cells. See, e.g., U.S. Pat. No. 5,292,498 to Boucher.
Existence of a G-protein-coupled receptor that selectively recognizes uridine 5'-diphosphate (UDP) was originally established in studies of a receptor natively expressed by C6-2B rat glioma cells. E. R. Lazarowski et al. J. Biol. Chem. 269, 11830-11836 (1994). The P2Y.sub.6 receptor was recently cloned by K. Chang et al., J. Biol. Chem. 270, 26152-26158 (1995). This receptor was subsequently shown to be selectively activated by UDP, and to be the UDP receptor natively expressed in C6-2B cells. R. A. Nicholas et al., Mol. Pharmacol. 50, 224-229 (1996). The failure to identify this receptor in previous studies of mammalian tissues likely has been a consequence of the lack of availability of potent selective agonists for uridine nucleotide receptors, and the low chemical and metabolic stability of the available nucleotides. It was originally reported that UDP stimulated inositol phosphate accumulation in human airway epithelial cells by low potency activation of the P2Y.sub.2 receptor. E. R. Lazarowski et al. Br. J. Pharmacol. 116, 1619-1627 (1995); H. A. Brown et al., Mol. Pharmacol. 40, 648-655 (1991). However, it has been recently demonstrated that UDP is in fact not an agonist at the P2Y.sub.2 receptor (Nicholas et al., supra) and that the previously observed effect of UDP at P2Y.sub.2 receptors can be explained by the presence of small amounts of contaminating UTP in UDP solutions and/or by conversion of UDP to UTP by cell surface nucleoside diphosphokinase.
Despite the evidence related to the P2Y.sub.6 receptor and its relationship to UDP, it has heretofore not been recognized that this relationship may be useful in the treatment of airway disease.